Compositions and methods for anti-lyst immunomodulation

Abstract

Excessive or repeated activation of inflammatory and pro-coagulant mechanisms at the site of tissue injury contributes to the development scar tissue that can lead to intimal hyperplasia and fibrotic disease. It has been established that inhibition of the LYST protein is associated with reduced inflammatory responses and reduced platelet activation at the site of tissue damage. Compositions and methods for inhibition of the expression and function of the LYST protein are described. The compositions and methods can be useful for the modulation of immune processes that contribute to formation of neointima and fibroproliferative disorders by altering macrophage, platelet and natural killer cell function to create a pro-regenerative immune response.

1 - 24 . (canceled) 
     
     
         25 . A method of reducing or preventing macrophage infiltration, scar formation, or stenosis in a subject, comprising
 administering to a subject up to three days prior to surgery, at the time of surgery, or up to 14 days after surgery an effective amount of a composition comprising:
 a) an inhibitor of lysosomal trafficking regulator (LYST) inhibiting LYST transcript or LYST protein, in an amount effective to reduce or prevent macrophage infiltration, natural killer cell activation, and to reduce or prevent platelet activation in the subject; and 
 b) a physiologically acceptable carrier, 
   wherein the amount of the LYST inhibitor does not prevent vascular neotissue formation in the subject,   optionally in combination with one or more additional therapeutic agents,   wherein the LYST inhibitor is administered in an amount and at a time effective to decrease scar formation, myocardial infarction, scarring adhesions, and liver fibrosis or to reduce or prevent platelet activation that could lead to arterial or venous thrombosis in a subject.   
     
     
         26 . The method of  claim 25 , wherein the composition is in a dosage effective to reduce or prevent macrophage infiltration. 
     
     
         27 . The method of  claim 25 , wherein the composition is in a dosage effective to reduce or prevent platelet activation. 
     
     
         28 . The method of  claim 25 , wherein the composition further comprises a delivery vehicle selected from the group consisting of nanoparticles, microparticles, micelles, emulsions, synthetic lipoprotein particles, liposomes, carbon nanotubes, gels, or coatings. 
     
     
         29 . The method of  claim 25 , wherein the one or more additional therapeutic agents are selected from the group consisting of anti-neointima agents, chemotherapeutic agents, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, immune-suppressants, cytokines, chemokines, and growth factors. 
     
     
         30 . The method of  claim 25 , wherein the composition is administered with a vascular graft or medical device. 
     
     
         31 . The method of  claim 30  wherein the composition is coated onto or incorporated into the graft or device. 
     
     
         32 . The method of  claim 30 , wherein the medical device is selected from the group consisting of stents, implants, needles, cannulas, catheters, shunts, balloons, and valves. 
     
     
         33 . The method of  claim 30 , wherein the medical device is a stent. 
     
     
         34 . The method of  claim 33 , wherein the medical device is a drug eluting stent that elutes the composition. 
     
     
         35 . The method of  claim 30 , wherein the vascular graft is an autologous, preserved autologous, allogeneic, xenogenic or synthetic graft. 
     
     
         36 . The method of  claim 25 , comprising administering to the subject in need thereof one or more additional therapeutic agents. 
     
     
         37 . The method of  claim 25  wherein the subject is at risk of or has restenosis or other vascular proliferation disorder. 
     
     
         38 . The method of  claim 25  wherein the subject has undergone or is undergoing vascular trauma, angioplasty, vascular surgery, or transplantation arteriopathy. 
     
     
         39 . The method of  claim 25 , wherein the composition is used to reduce or prevent the formation of scar tissue, promote healing, reduce or prevent the development of hypertrophic scarring, keloids, or adhesions, reduce or prevent fibrosis of the liver, fibrosis of the lungs, fibrosis of the heart or fibrosis of the kidneys, reduce or prevent neointima formation, stenosis or restenosis, reduce or prevent thrombosis, or any combination thereof in a subject relative to an untreated control subject. 
     
     
         40 . The method of  claim 25 , wherein reducing or preventing the formation of scar tissue promotes integration but blocks encapsulation of one or more bio-prosthesis devices selected from the group consisting of pacemakers, nerve stimulators, replacement heart valves and artificial joints. 
     
     
         41 . The method of  claim 25 , wherein reducing or preventing the formation of scar tissue is effective to treat or prevent neointima formation at a site of implantation of a vascular implant, a site of vascular injury, or a site of surgery in a subject, relative to an untreated control subject. 
     
     
         42 . The method of  claim 37 , wherein the composition is used to reduce the expression of platelet derived growth factor, transforming growth factor beta, or combination thereof in a subject relative to an untreated control subject. 
     
     
         43 . A method of reducing stenosis or restenosis of a vascular graft comprising treating the graft ex vivo with a composition comprising:
 a) an inhibitor of lysosomal trafficking regulator (LYST) inhibiting LYST transcript or LYST protein, in an amount effective to reduce or prevent macrophage infiltration, natural killer cell activation, and to reduce or prevent platelet activation in the subject; and   b) a physiologically acceptable carrier,   wherein the amount of one or more inhibitors of LYST does not prevent vascular neotissue formation in the subject following graft implantation,   prior to implantation of the graft into a subject.